Abstract Quorum Sensing (QS), or bacterial communication by intercellular chemical signaling, is a process common to many (if not most) bacterial species; yet, it is unclear how QS signaling pathways contribute to virulence in many clinically significant pathogens. The Federle lab has helped to characterize a family of transcriptional regulators, known as Rgg proteins, as mediators of QS. We and others have shown the importance of Rgg proteins in multiple species of streptococci in regulating expression of genes that may enhance their ability to colonize and infect the host. Rgg proteins are known to regulate genes important for 1) controlling virulence; 2) promoting the development of resistance to lysozyme, a host-produced antimicrobial enzyme; 3) stimulating the formation of biofilms, or protective bacterial communities; 4) initiating the development of natural competence to take up DNA from the environment; and 5) promoting the ability to adhere to epithelial cells. The role of the Rgg proteins in the pathogenic lifestyle of the clinically significant pathogen S. pneumoniae has yet to be investigated, but published genome-level mutagenesis studies indicate Rgg proteins in this organism are critical in in vivo animal models of infection. We have constructed isogenic mutants for each Rgg protein important in vivo and have performed transcriptomic analysis to identify gene targets under Rgg- regulation. Our analysis has revealed 18 gene targets under regulation by the Rgg protein SP_0141 in the pneumococcal encapsulated strain TIGR4 (serotype 4). We are in the process of testing gene targets of interest in order to understand Rgg-mediated QS and its role in virulence. We will then explore the consequences of using QS to regulate mechanisms of pathogenesis in the presence of immune surveillance. Understanding the molecular networks under QS regulation and the advantage of using QS in the host will provide support for the possibility of modulating QS as an effective strategy for combatting pathogens.